Phase 0 clinical trials: Theoretical and practical implications in oncologic drug development

Drug discovery and development has become a risky, expensive, and protracted process, with the cost of introducing a new drug to the market going as high as US$2 billion and the entire process taking at least 10-15 years. Great advances in biomedical research in recent years have not resulted in translation into medical product development, and there has been substantial decline in both new drug applications and biological license applications. To address this so-called "pipeline problem," both the US Food and Drug Administration and its European counterpart, the European Agency for the Evaluation of Medicinal Products (now European Medicines Agency) endorsed the concept of Phase 0 studies (also known as exploratory investigational new drug studies), aimed towards identifying, early in the process of drug development, viable candidates and eliminating those lacking promise. Primary study endpoints of trials conducted under an exploratory investigational new drug can include evaluation of analogs for lead selection, modulation of a molecular target in vivo, whole-body imaging for tissue distribution/target binding affinity, and agent pharmacokinetics. Phase 0 trials bridge the gap between traditional preclinical testing and clinical studies and are intended to provide a better understanding of a new compound's pharmacokinetics, pharmacodynamics, and target localization before initiation of Phase I trials. When such information can be obtained earlier, decisions regarding drug development can also be made at an earlier point in time, potentially reducing costs of initial preclinical studies and time-to-first-in-human testing. This review provides an overview of the various conditions that have to be met in order for a Phase 0 trial to be successful, citing examples of two candidate drugs that have been further developed after Phase 0 trials in oncology. Challenges and opportunities with Phase 0 trials are discussed, including ethical issues associated with trials that have no therapeutic or diagnostic intent.

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